Pathway-dependent cold activation of heat-responsive TRPV channels

The homotetrameric thermosensitive transient receptor potential vanilloid 1–4 (TRPV1-4) channels in sensory neurons are highly responsive to heat stimuli. However, their primary heat sensors or triggers for heat activation have not been examined for cold activation. In this study, cold activation of minimal TRPV1 without the pore turret was compared with that of full-length human TRPV3. The former followed a pathway from the putative heat activation starter, while the latter tracked a different pathway starting far from the assumed heat activation point. The results showed that the former shared temperature sensitivity with heat activation while the latter did not. Therefore, this mirrored thermosensitivity can be used to confirm the location of the primary thermal sensor for TRPV1 or TRPV3, and potentially define the primary thermal sensor of other thermosensitive proteins like TRPV2 or TRPV4 once the same heat capacity mechanism is applied. (142 words)